Pyrrolo-pyridine derivative compound, method for preparing same, and pharmaceutical composition containing same as active ingredient for prevention or treatment of protein kinase-related diseases

Patent metadata

Field	Value
Publication number	US-11117892-B2
Application number	US-201816495455-A
Country	US
Kind code	B2
Filing date	Mar 23, 2018
Priority date	Mar 23, 2017
Publication date	Sep 14, 2021
Grant date	Sep 14, 2021

Abstract

The present invention relates to a pyrrolo-pyridine derivative compound, a method for preparing the same, and a pharmaceutical composition containing the same as an active ingredient for the prevention or treatment of protein kinase-related diseases. A compound represented by chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, according to the present invention, has excellent inhibitory activity against various protein kinases including DYRK1A, and therefore, the pharmaceutical composition containing the same as an active ingredient can be favorably used in the treatment or prevention of protein kinase-related diseases. Particularly, the pharmaceutical composition can be effectively used in the prevention, treatment, or alleviation of Alzheimer's disease, dementia, or Alzheimer's dementia.

First claim

What is claimed is:

1. A compound represented by chemical formula 1 below, an optical isomer thereof or a pharmaceutically acceptable salt thereof:

In chemical formula 1,
Z is cyano (—CN); or straight or branched C 1 -C 3 alkyl substituted with one or more halogens;
X is —NR a —, —O— or —S—, wherein R a is hydrogen or straight or branched C 1 -C 10 alkyl, wherein, the alkyl can be substituted with one or more substituents selected from the group consisting of —OH and C 1 -C 3 alkoxy;
R 1 is straight or branched C 1 -C 10 alkyl, C 3 -C 8 cycloalkyl or C 6-14 aryl, wherein, the alkyl or cycloalkyl can be substituted with one or more substituents selected from the group consisting of —OH, and, straight or branched C 1 -C 3 alkyl and C 1 -C 3 alkoxy, and the aryl can be substituted with one or more substituents selected from the group consisting of straight or branched C 1 -C 3 alkyl and straight or branched C 1 -C 3 alkoxy, nonsubstituted or substituted with one or more halogens;
or, R a can form nonsubstituted or substituted 5-8 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S along with R 1 and nitrogen atom to which they are attached, and the substituted heterocycloalkyl can be substituted with one or more substituents selected from the group consisting of straight or branched C 1 -C 6 alkyl and straight or branched C 1 -C 6 alkoxy; and

wherein, each R 2 , R 4 , R 6 , R 8 , R 11 , R 17 , R 23 and R 24 are independently one or more substituents selected from the group consisting of hydrogen, halogen, straight or branched C 1 -C 6 alkyl and straight or branched C 1 -C 6 alkoxy;
R 3 , R 5 , R 7 and R 9 are independently hydrogen; straight or branched C 1 -C 6 alkyl or alkoxy; 3-8 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N and O; or —(C═O)NR 26 R 27 , wherein R 26 and R 27 are independently hydrogen, straight or branched C 1 -C 3 alkyl or 3-8 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N and O substituted with 3-5 membered heterocycloalkyl containing one or more oxygen atoms, or, R 26 and R 27 form 3-8 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N and O along with nitrogen atom to which they are attached, wherein, the alkyl or heterocycloalkyl is substituted with one or more substituents selected from the group consisting of —CN, halogen, straight or branched C 1 -C 3 alkyl, and, 3-6 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N and O nonsubstituted or substituted with one or more straight or branched C 1 -C 3 alkyl
R 10 is —CR 28 R 29 —CN, wherein R 28 and R 29 are independently hydrogen or straight or branched C 1 -C 3 alkyl,
R 12 , R 13 , R 14 , R 15 , R 18 , R 19 , R 20 and R 21 are independently hydrogen or straight or branched C 1 -C 3 alkyl, or, two of R 12 , R 13 , R 14 , R 15 , R 18 , R 19 , R 20 and R 21 bonded to the same carbon can form carbonyl along with the carbon to which they are attached, and
R 16 , R 22 and R 25 are independently hydrogen or straight or branched C 1 -C 3 alkyl, wherein the alkyl can be substituted with one or more halogens.

2. The compound, the optical isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1 , wherein:
Z is —CN or methyl substituted with one or more halogens;
X is —NR a — or —O—, wherein R a is hydrogen or straight or branched C 1 -C 6 alkyl, wherein, the alkyl can be substituted with one or more substituents selected from the group consisting of —OH and C 1 -C 3 alkoxy;
R 1 is straight or branched C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or C 6-10 aryl, wherein, the alkyl can be substituted with one or more substituents selected from the group consisting of —OH, methyl and methoxy, and the aryl can be substituted with one or more substituents selected from the group consisting of methyl and methoxy, nonsubstituted or substituted with one or more halogens;
or, R a can form nonsubstituted or substituted 5-6 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S along with R 1 and nitrogen atom to which they are attached, and the substituted heterocycloalkyl can be substituted with one or more substituents selected from the group consisting of straight or branched C 1 -C 3 alkyl and straight or branched C 1 -C 3 alkoxy; and

wherein, R 2 , R 4 , R 6 , R 8 , R 11 , R 17 , R 23 and R 24 are independently one or more substituents selected from the group consisting of hydrogen, halogen, straight or branched C 1 -C 3 alkyl and straight or branched C 1 -C 3 alkoxy;
R 3 , R 5 , R 7 and R 9 are independently hydrogen, straight or branched C 1 -C 3 alkyl or alkoxy, morpholinyl, piperazinyl, piperidinyl or —(C═O)NR 26 R 27 ,
wherein R 26 and R 27 are independently hydrogen, methyl, morpholinyl, piperazinyl or piperidinyl, or, R 26 and R 27 form morpholinyl, piperazinyl or piperidinyl along with nitrogen atom to which they are attached, wherein, the C 1 -C 3 alkyl, morpholinyl, piperazinyl or piperidinyl can be substituted with one or more substituents selected from the group consisting of —CN, fluoro, oxetanyl, morpholinyl, piperazinyl, and, nonsubstituted or methyl substituted piperidinyl,
R 10 is —CR 28 R 29 —CN, wherein R 28 and R 29 are independently hydrogen, methyl or ethyl,
R 12 , R 13 , R 14 , R 15 , R 18 , R 19 , R 20 and R 21 are independently hydrogen, methyl or ethyl, or, two of R 12 , R 13 , R 14 , R 15 , R 18 , R 19 , R 20 and R 21 bonded to the same carbon can form carbonyl along with the carbon to which they are attached, and
R 16 , R 22 and R 25 are independently hydrogen, methyl nonsubstituted or substituted with one or more halogens or ethyl nonsubstituted or substituted with one or more halogens.

3. The compound, the optical isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1 , wherein:
Z is —CN or —CF 3 ;
X is —NR a — or —O—, wherein R a is hydrogen or methyl;
R 1 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl,

1-methylcyclopropyl, or, phenyl substituted with one or more CF 3 ;
or, R a can form morpholinyl along with R 1 and nitrogen atom to which they are attached; and

wherein, R 2 , R 4 , R 6 , R 8 , R 11 , R 17 , R 23 and R 24 are independently one or more substituents selected from the group consisting of hydrogen, chloro, fluoro, methyl and methoxy;
R 3 and R 7 are independently methoxy,

R 5 and R 9 are independently methyl, isopropyl,

R 10 is —CR 28 R 29 —CN, wherein R 28 and R 29 are independently hydrogen or methyl,
R 12 , R 13 , R 14 , R 15 , R 18 , R 19 , R 20 and R 21 are independently hydrogen or methyl, or, two of R 12 , R 13 , R 14 , R 15 , R 18 , R 19 , R 20 and R 21 bonded to the same carbon can form carb

Assignees

• Daegu Gyeongbuk Medical Innovation Found
• Korea Res Inst Bioscience & Biotechnology
• Daegu Gyeongbuk Inst Science & Tech

Inventors

• Choi Hwan Geun
• Ko Eunhwa
• Cho Joong-Heui
• Son Jung Beom
• Ko Yi Kyung
• Park Jin-Hee
• Kim So Young
• Kang Seock Yong
• Lee Seungyeon
• Ryu Hee Yoon
• Kim Nam Doo
• Kim Sang Bum
• Lee Sun-Hwa
• Kim Dayea
• Lee Sun Joo
• Cho Sungchan
• Lee Kyu-Sun
• Yu Kweon
• Choi Miri
• Koo Ja Wook
• Hoe Hyang-Sook

Classifications

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/538

  ortho- or peri-condensed with carbocyclic ring systems · CPC title